ISAL 2023 | Novel mitochondrial targets being explored in AML & strategies to overcome resistance to venetoclax

So this is all based on the change in leukemia treatment that came with the introduction of venetoclax. So we were very much involved in that. We published the first paper in 2006 and it took another 11 years to get FDA approval for venetoclax in AML. The benefit is we have very high remission rates now, response rates of 70 to 90% of patients even at advanced age, patients who were never treated before. But the majority of these patients are relapsing. So my talk today was addressing some of the resistance mechanisms to venetoclax. Ventoclax targets BCL2 and there are other mechanisms in the apoptosis pathways that cause resistance. The main factor is probably MCL1. MCL1 is also a mitochondrial protein and it can be targeted in many ways and I expanded on that.

So the most direct way is to use a similar approach that was used for venetoclax, namely getting into the so-called BH3 groove of MCL1 and to displace and separate the poor and anti-apoptotic proteins so that the pro-apoptotic proteins can cause apoptosis. That’s a direct way these drugs are under development. There has been some toxicity observed and this has to be worked out if there is cardiotoxicity or not with these agents. And the indirect way of targeting MCL1 would be to degrade it. And we devised a way five years ago to activate p53 and p53 then would phosphorylate MCL1 and after a second phosphorylation step it gets degraded. P53 also induces poor apoptotic molecules like Noxa and Puma and they inactivate the anti-apoptotic function of MCL1. So on one hand we are degrading MCL1, on the other hand we are, whatever is left, we inactivate it. So this has been tested in a clinical trial which was published in December last year in Blood and we had very good response rates of 40 to 80% depending on the molecular subgroup. So this is something I would propose to continue with MDM2 inhibitors in combination with BCL2 inhibitors. So I’ve worked on these MDM2 inhibitors that activate p53 for many years, 20 years. And the clinical trial results have not been overwhelming for monotherapy with these agents. So what we devised was a way to keep the p53 protein in the nucleus because it’s a transcription factor and we could do that by blocking a molecule that’s called XPO1, exportin 1, which pumps out…these proteins out of the nucleus into the cytoplasm where they can’t work as transcription factors. So we keep p53 in the nucleus and we get a 30 to 60 fold increase in p53 targets, very effective. So we combined now XPO1 inhibition with BCL2 inhibition and we got very synergistic, very good survival data in mice carrying in human cells. These are so-called PDX models. So they are patient-derived models, not cell lines, which are to a degree predictive of response in the clinic.

My talk was about new targets in mitochondria and one of them is to target oxidative phosphorylation, which is a major resistance factor. And there are different components that are very well understood complex I-V, and when one inhibits complex I, there have been deleterious consequences for patients, namely major neurotoxicity and death, so this is not the way forward. And at MD Anderson, we spent several years developing a highly specific drug which then had no therapeutic window. The toxicity was much too great. So we thought about other ways to target oxidative phosphorylation and one is to use proteases in mitochondria that digest the proteins that are part of this complex, and one of these proteases is called ClpP. We have a drug that we developed that targets and activates this protease. It now sucks in misfolded proteins and destroys them and therefore inhibits oxidative phosphorylation. Another target is called LONP1. We worked on that 20 years ago, we forgot about it, now we will reactivate that in collaboration with a colleague in Canada, Dr Shima. And again, the idea is to target oxidative phosphorylation in an indirect manner without hopefully too much toxicity. And finally, I talked about a new mode of cell death beyond apoptosis. Apoptosis has been very well established for many years. Ten years ago, the first paper was published on what’s called ferroptosis. Ferroptosis, as the name implies, is dependent on iron, it is very early stage. There is a target called GPX4, drugs have been developed to inhibit it and what we have shown is that we get cytochrome C release from mitochondria independent and through a different mechanism independent what venetoclax will do. So our plan is to combine these two approaches and be sure already that they’re synergistic in preclinical models. But hopefully we will one day be able to bring these GPX4 or other ferroptosis-targeting agents into the clinic and then combine them with venetoclax.